PHARMACEUTICAL COMPOSITIONS COMPRISING 4-((6bR,10aS)-3-METHYL2,3,6b,9,10,10a-HEXAHYDRO-1H-PYRIDO[3&#39;,4&#39;:4,5]PYRROLO[1,2,3-de]QUINOXALIN8(7H)-YL)-1-(4-((6bR,10aS)-3-METHYL-2,3,6b,9,10,10a-HEXAHYDRO-1HPYRIDO[3&#39;,4&#39;:4,5]PYRROLO[1,2,3-de]QUINOXALIN-8(7H)-YL)PHENYL)BUTAN-1-ONE FOR TREATING CONDITIONS OF THE CENTRAL NERVOUS SYSTEM AND CARDIAC DISORDERS

ABSTRACT

The invention relates to pharmaceutical compositions comprising the compound of Formula I,and new methods and uses pertaining thereto, and pharmaceutical compositions thereof, such as methods of use in the treatment of diseases involving the 5-HT receptor, the serotonin transporter (SERT), and/or pathways involving dopamine D2 receptor signaling, sodium channel activity, and/or norepinephrine transporter activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is an international application which claims priorityto and the benefit of U.S. Provisional Application Ser. No. 62/946,568,filed on Dec. 11, 2019, the contents of which are hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to a new compound, a particular substitutedheterocycle fused gamma-carboline, and new methods and uses pertainingthereto, and pharmaceutical compositions thereof, such as methods of usein the treatment of diseases involving the 5-HT receptor, the serotonintransporter (SERT), and/or pathways involving dopamine D₂ receptorsignaling, sodium channel activity, and/or norepinephrine transporteractivity, e.g., diseases or disorders such as anxiety, psychosis,schizophrenia, sleep disorders, sexual disorders, migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility andobesity; depression and mood disorders associated with psychosis orParkinson's disease; psychosis such as schizophrenia associated withdepression; bipolar disorder; mood disorders; and other psychiatric andneurological conditions, as well as to combinations with other agents.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT₂ receptors, particularly 5-HT_(2A) and 5-HT_(2C)receptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compoundsuseful for the treatment of disorders associated with 5-HT_(2A) receptormodulation such as obesity, anxiety, depression, psychosis,schizophrenia, sleep disorders, sexual disorders migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility,and obesity. Methods of making substituted heterocycle fusedgamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders are disclosed in U.S. Pat. Nos. 7,081,455; 7,071,186;7,183,282; 8,309,722; 8,779,139; 9,315,504; 9,751,883; 10,221,176; andin applications PCT/US2019/36593 and Ser. No. 16/438,163, the contentsof each of which are hereby incorporated by reference in theirentireties.

In addition, U.S. Pat. No. 8,598,119 discloses use of particularsubstituted heterocycle fused gamma-carbolines for the treatment of acombination of psychosis and depressive disorders as well as sleep,depressive and/or mood disorders in patients with psychosis orParkinson's disease. In addition to disorders associated with psychosisand/or depression, this patent application discloses and claims use ofthese compounds at a low dose to selectively antagonize 5-HT_(2A)receptors without affecting or minimally affecting dopamine D₂receptors, thereby useful for the treatment of sleep disorders withoutthe side effects associated with high occupancy of the dopamine D₂pathways or side effects of other pathways (e.g., GABA_(A) receptors)associated with convention sedative-hypnotic agents (e.g.,benzodiazepines) including but not limited to the development of drugdependency, muscle hypotonia, weakness, headache, blurred vision,vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains,and chest pains. U.S. Pat. No. 8,648,077 also discloses of methods ofpreparing toluenesulfonic acid addition salt crystals of thesesubstituted heterocycle fused gamma-carbolines.

One particular fused heterocycle gamma carboline,4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone,is disclosed in, for example, US 2011/0071080, US 2015/0072964, US2015/0080404, and US 2016/0310503. This compound is a potent serotonin5-HT_(2A) receptor antagonist, dopamine receptor D1 and D2 modulator,and scrotonin transporter (SERT) antagonist.

4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone,also known as lumateperone, has also been approved for the treatment ofschizophrenia in the United States (as CAPLYTA®), and it has completedPhase II and/or Phase III clinical trials for the treatment of agitationassociated with dementia, and bipolar depression.

There remains a need for additional compounds having strong serotoninreceptor, serotonin transporter (SERT), and/or dopamine D₂ receptoractivities, and other biological activities.

SUMMARY OF THE INVENTION

The present disclosure relates to the Compound of Formula I, in free orpharmaceutically acceptable salt form, as shown below:

The compound of the present disclosure has been unexpectedly found tohave potent affinity for, or activity at, serotonin receptors (e.g.,5-HT_(2A), 5-HT_(2B)), serotonin transporters (SERT), dopamine receptors(e.g., D2), sodium channels (e.g., via site 2 binding), andnorepinephrine transporters. This compound has been disclosed assynthetic by-product in the synthesis of lumateperone, e.g., inWO2019/241278 and US 2020/0102309, the contents of which are herebyincorporated by reference in its entirety.

In a first aspect, the present disclosure provides the compound(Compound 1) of Formula I:

in free or salt form (e.g., pharmaceutically acceptable salt form), forexample in an isolated or purified free or salt form.

The present disclosure provides additional exemplary embodiments of theCompound of Formula I, in free or salt form, for example in an isolatedor purified free or salt form, including:

-   -   1.1 Compound 1 in free form (i.e., free base form);    -   1.2 Compound 1 in salt form, e.g., pharmaceutically acceptable        salt form;    -   1.3 Compound 1.2, wherein the salt is an acid addition salt        selected from hydrochloric, hydrobromic, sulfuric, sulfamic,        phosphoric, nitric, acetic, propionic, succinic, glycolic,        stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,        malcic, hydroxymalcic, phenylacetic, glutamic, benzoic,        salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,        toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,        isethionic, and the like;    -   1.4 Compound 1.3, in toluenesulfonic acid addition salt form,        e.g., as a monotosylate salt, ditosylate salt, tritosylate salt,        or tetratosylate salt, or any combination thereof;    -   1.5 Compound 1, or any of 1.1-1.4, in solid form;    -   1.6 Compound 1 or any of 1.1-1.5, in substantially pure        diastereomeric form (i.e., substantially free from other        diastereomers, including enantiomers);    -   1.7 Compound I or any of 1.1-1.6, having a diastereomeric excess        of greater than 70%, preferably greater than 80%, more        preferably greater than 90% and most preferably greater than        95%;    -   1.8 Compound 1 or any of 1.1-1.7 in isolated or purified form        (e.g., in at least 90% pure form, or at least 95%, or at least        96%, or at least 97%, or at least 98%, or at least 99%);    -   1.9 Compound 1 or any of 1.1-1.8, wherein the compound has        greater than 50% incorporation of deuterium at one or more of        the hydrogen atom positions of the structure (i.e., greater than        50 atom % D), e.g., greater than 60%, or greater than 70%, or        greater than 80%, or greater than 90% or greater than 95%, or        greater than 96%, or greater than 97%, or greater than 98%, or        greater than 99%;    -   1.10 Compound 1.9, wherein the Compound 1 is a compound of        Formula:

-   -   1.11 Compound 1.10, wherein D indicates an atomic position        having at least 50% incorporation of deuterium, e.g., at least        60%, or at least 70%, or at least 80%, or at least 90% or at        least 95%, or at least 96%, or at least 97%, or at least 98%, or        at least 99%, up to 100 atom % deuterium.

In a second aspect, the present disclosure provides a pharmaceuticalcomposition (Pharmaceutical Composition 2) comprising a Compound 1 orany of 1.1-1.11, e.g., in admixture with a pharmaceutically acceptablediluent or carrier. The present disclosure provides additional exemplaryembodiments of Pharmaceutical Composition 2, including:

-   -   2.1 Pharmaceutical Composition 2, wherein the Compound of        Formula 1 or any of    -   1.1-1.11 is in solid form;    -   2.2 Pharmaceutical Composition 2 or 2.1, wherein the compound of        Formula 1 is in pharmaceutically acceptable salt form, e.g., a        compound selected from Compound 1.3 or 1.4, or any of Compounds        1.5-1.11;    -   2.3 Pharmaceutical Composition 2 or any of 2.1 to 2.2, wherein        the pharmaceutical composition further comprises the compound of        Formula II:

-   -   -   in free or pharmaceutically acceptable salt form;

    -   2.4 Pharmaceutical Composition 2.3, wherein the compound of        Formula II is in pharmaceutically acceptable salt form, e.g.,        toluenesulfonic acid addition salt form (e.g., monotosylate or        ditosylate salt form);

    -   2.5 Pharmaceutical Composition 2.3 or 2.4, comprises the        compound of Formula I and the compound of Formula II in a weight        ratio of from 1:200 to 1:2000, e.g., 1:245 to 1:1000, or 1:250        to 1:550, or 1:285 to 1:460, or 1:300 to 1:500;

    -   2.6 Pharmaceutical Composition 2 or any of 2.1 to 2.2, wherein        the pharmaceutical composition does not comprise the compound of        Formula II;

    -   2.7 Pharmaceutical Composition 2 or any of 2.1-2.6, wherein the        pharmaceutically acceptable diluent or carrier is selected from        one or more of (a) diluent/filler (e.g., cellulose or        microcrystalline cellulose (e.g., silicified microcrystalline        cellulose), mannitol, lactose monohydrate, dicalcium phosphate,        or isomalt), (b) binder (e.g., hydroxypropyl cellulose,        hydroxypropyl methyl cellulose, copovidone), (c) disintegrant        (e.g., sodium starch glycolate, crospovidone or croscarmellose        sodium), (d) lubricant (e.g., magnesium stearate or glyceryl        monostearate), (e) glidant (e.g., silicon dioxide or talc), (f)        effervescent, (g) polymer, (h) plasticizer, (i) drying agent or        desiccant, (j) humectant (e.g., polyol), (k) wetting agent, (1)        anti-oxidant (e.g., BHT, citric acid, propyl gallate, ascorbic        acid or sodium metabisulfite), (m) thickening agent (e.g.,        gelling agent), (n) surfactant, (o) buffer, (p) sweetener or        flavor, and (q) dye or colorant, or any other agents as        described in PCT/US2019/049061, PCT/US2019/049062 or U.S. Pat.        No. 10,695,345, the contents of each of which are hereby        incorporated by reference in their entireties.

In a preferred embodiment, the Pharmaceutical Composition of the presentdisclosure comprises a Compound of Formula 1 or 1.1-1.11, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier.

In a further embodiment, the Pharmaceutical Compositions of the presentdisclosure, are sustained or delayed release formulations, for example,depot formulations. In one embodiment, the depot formulation(Pharmaceutical Composition 2.8) is the Pharmaceutical Composition 2 orany of 2.1-2.7, preferably in free or pharmaceutically acceptable saltform, and preferably in admixture with a pharmaceutically acceptablediluent or carrier, e.g., providing sustained or delayed release as aninjectable depot.

In a further embodiment, the present disclosure provides PharmaceuticalComposition 2.9, which is Pharmaceutical Composition 2 or any of2.1-2.8, wherein the Compound of Formula 1 et seq. is in a polymericmatrix. In one embodiment, the Compound of the present disclosure isdispersed or dissolved within the polymeric matrix. In a furtherembodiment, the polymeric matrix comprises standard polymers used indepot formulations such as polymers selected from a polyester of ahydroxyfatty acid and derivatives thereof, or a polymer of an alkylalpha-cyanoacrylate, a polyalkylene oxalate, a polyortho ester, apolycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronicacid ester, and mixtures thereof. In a further embodiment, the polymeris selected from a group consisting of polylactide, poly d,l-lactide,poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. Inanother embodiment, the polymer is selected form poly(glycolic acid),poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxanone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and natural polymers including albumin, casein, andwaxes, such as, glycerol mono- and distearate, and the like. In apreferred embodiment, the polymeric matrix comprisespoly(d,l-lactide-co-glycolide).

For example, in one embodiment of Pharmaceutical Composition 2.9, theCompound is the Compound of Formula 1 or 1.1 et seq., in free orpharmaceutically acceptable salt form. In another example ofPharmaceutical Composition 2.9, the Compound is the Compound of Formula1 or 1.1 et seq. in free or pharmaceutically acceptable salt form, inadmixture with a pharmaceutically acceptable diluent or carrier. Inanother example of Pharmaceutical Composition 2.9, the Compound is theCompound of Formula 1 or 1.1 et seq., in admixture with apharmaceutically acceptable diluent or carrier, wherein the diluent orcarrier comprises a polymeric matrix, optionally wherein the polymericmatrix comprises a poly(d,l-lactide-co-glycolide) copolymer.

In some embodiments, Pharmaceutical Composition 2.9 is particularlyuseful for sustained or delayed release, wherein the Compound of thepresent disclosure is released upon degradation of the polymeric matrix.These Compositions may be formulated for controlled- and/orsustained-release of the Compounds of the present disclosure (e.g., as adepot composition) over a period of up to 180 days, e.g., from about 14to about 30 to about 180 days. For example, the polymeric matrix maydegrade and release the Compounds of the present disclosure over aperiod of about 30, about 60 or about 90 days. In another example, thepolymeric matrix may degrade and release the Compounds of the presentdisclosure over a period of about 120, or about 180 days.

In still another embodiment, the Pharmaceutical Compositions of thepresent disclosure, for example the depot composition of the presentdisclosure, e.g., Pharmaceutical Composition 2.8, is formulated foradministration by injection.

In further embodiment, the present disclosure provides the Compounds ofFormulas 1 or 1.1 et seq. as hereinbefore described, in an osmoticcontrolled release oral delivery system (OROS), which is described U.S.Pub. No. 2009/0202631, the contents of which are incorporated byreference in its entirety. Therefore in one embodiment of the seventhaspect, the present disclosure provides a pharmaceutical composition ordevice comprising (a) a gelatin capsule containing a Compound of any ofFormulas 1 or 1.1 et seq. in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention, as hereinbeforedescribed; (b) a multilayer wall superposed on the gelatin capsulecomprising, in outward order from the capsule: (i) a barrier layer, (ii)an expandable layer, and (iii) a semipermeable layer; and (c) andorifice formed or formable through the wall (Pharmaceutical CompositionP.1).

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a gelatin capsule containing a liquid, theCompound of Formulas 1 or 1.1 et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,e.g., any of Pharmaceutical Composition 2 or 2.1-2.9, the gelatincapsule being surrounded by a composite wall comprising a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting the barrier layer, a semi-permeable layer encompassingthe expandable layer, and an exit orifice formed or formable in the wall(Pharmaceutical Composition P.2).

In still another embodiment, the invention provides a compositioncomprising a gelatin capsule containing a liquid, the Compound ofFormulas 1 or 1.1 et seq. in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention, e.g., any ofPharmaceutical Composition 2 or 2.1-2.9, the gelatin capsule beingsurrounded by a composite wall comprising a barrier layer contacting theexternal surface of the gelatin capsule, an expandable layer contactingthe barrier layer, a semipermeable layer encompassing the expandablelayer, and an exit orifice formed or formable in the wall, wherein thebarrier layer forms a seal between the expandable layer and theenvironment at the exit orifice (Pharmaceutical Composition P.3).

In still another embodiment, the invention provides a compositioncomprising a gelatin capsule containing a liquid, the Compound ofFormulas 1 or 1.1 et seq. in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention, e.g., any ofPharmaceutical Composition 2 or 2.1-2.9, the gelatin capsule beingsurrounded by a barrier layer contacting the external surface of thegelatin capsule, an expandable layer contacting a portion of the barrierlayer, a semi-permeable layer encompassing at least the expandablelayer, and an exit orifice formed or formable in the dosage formextending from the external surface of the gelatin capsule to theenvironment of use (Pharmaceutical Composition P.4). The expandablelayer may be formed in one or more discrete sections, such as forexample, two sections located on opposing sides or ends of the gelatincapsule.

In a particular embodiment, the Compound of the present disclosure inthe Osmotic-controlled Release Oral Delivery System (i.e., inPharmaceutical Composition P.1-P.4) is in a liquid formulation, whichformulation may be neat, liquid active agent, liquid active agent in asolution, suspension, emulsion or self-emulsifying composition or thelike.

Further information on Osmotic-controlled Release Oral Delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in US 2001/0036472, the contents of which are incorporated byreference in its entirety.

Other Osmotic-controlled Release Oral Delivery System for the Compoundof 1 or 1.1 et seq. or the Pharmaceutical Composition of the presentdisclosure may be found in U.S. Pub. No. 2009/0202631, the contents ofwhich are incorporated by reference in their entirety. Therefore, inanother embodiment of the seventh aspect, the invention provides acomposition or device comprising (a) two or more layers, said two ormore layers comprising a first layer and a second layer, said firstlayer comprises the Compound of 1 or 1.1 et seq., in free orpharmaceutically acceptable salt form, or a Pharmaceutical Compositionas herein before described said second layer comprises a polymer; (b) anouter wall surrounding said two or more layers; and (c) an orifice insaid outer wall (Pharmaceutical Composition P.5).

Composition P.5 preferably utilizes a semi-permeable membranesurrounding a three-layer-core: in these embodiments the first layer isreferred to as a first drug layer and contains low amounts of drug(e.g., the Compound of 1 or 1.1 et seq.) and an osmotic agent such assalt, the middle layer referred to as the second drug layer containshigher amounts of drug, excipients and no salt; and the third layerreferred to as the push layer contains osmotic agents and no drug(Pharmaceutical Composition P.6). At least one orifice is drilledthrough the membrane on the first drug layer end of the capsule-shapedtablet.

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the Compound of the Invention in free orpharmaceutically acceptable salt thereof (Pharmaceutical CompositionP.7). Depending upon the relative viscosity of the first drug layer andsecond drug layer, different release profiles are obtained. It isimperative to identify the optimum viscosity for each layer. In thepresent invention, viscosity is modulated by addition of salt, sodiumchloride. The delivery profile from the core is dependent on the weight,formulation and thickness of each of the drug layers.

In a particular embodiment, the invention provides PharmaceuticalComposition P.7 wherein the first drug layer comprising salt and thesecond drug layer containing no salt. Pharmaceutical Composition P.5-P.7may optionally comprise a flow-promoting layer between the membrane andthe drug layers.

Pharmaceutical Compositions P.1-P.7 may generally be referred to asOsmotic-controlled Release Oral Delivery System Composition.

In a third aspect, the invention provides a method (Method 3) for thetreatment or prophylaxis of a central nervous system disorder or cardiacdisorder, comprising administering to a patient in need thereof aCompound of 1 or 1.1 et seq. or a Pharmaceutical Composition 2 or2.1-2.9 or P.1-P.7.

In a further embodiment of the third aspect, the present disclosureprovides Method 3, wherein the method is further as described asfollows:

-   -   3.1 Method 3, wherein the central nervous system disorder is a        disorder involving the serotonin 5-HT₂ receptor (e.g., 5-HT_(2A)        or 5-HT_(2B)), dopamine D2 receptor system, the serotonin        reuptake transporter (SERT), the norepinephrine reuptake        transported (NET), and/or the sodium ion channel (e.g., voltage        gated sodium channel), for example, as similarly described in US        2011/071080, the contents of which are herein incorporated by        reference in its entirety;    -   3.2 Method 3 or 3.1, wherein the central nervous system disorder        is a disorder selected from the group consisting of obesity,        anxiety, depression (for example refractory depression and/or        MDD (major depressive disorder)), psychosis (including psychosis        associated with dementia, such as hallucinations in advanced        Parkinson's disease or paranoid delusions), schizophrenia, sleep        disorders (particularly sleep disorders associated with        schizophrenia and other psychiatric and neurological diseases),        sexual disorders, migraine, conditions associated with cephalic        pain, social phobias, agitation in dementia (e.g., agitation in        Alzheimer's disease), agitation in autism and related autistic        disorders, gastrointestinal disorders such as dysfunction of the        gastrointestinal tract motility, and dementia, for example        dementia of Alzheimer's disease or of Parkinson's disease; and        mood disorders; obsessive-compulsive disorder (OCD),        obsessive-compulsive personality disorder (OCPD), general        anxiety disorder, social anxiety disorder, panic disorder,        agoraphobia, compulsive gambling disorder, compulsive eating        disorder, body dysmorphic disorder, hypochondriasis,        pathological grooming disorder, kleptomania, pyromania;        attention deficit-hyperactivity disorder (ADHD), attention        deficit disorder (ADD), impulse control disorder;        neurodegenerative disorders (e.g., Alzheimer's disease or        Parkinson's disease), orthostatic intolerance, pain disorders        (e.g., neuropathic pain, traumatic pain), substance abuse        disorders, and combination thereof;    -   3.3 Method 3 or 3.1, wherein the central nervous system disorder        is a disorder selected from the following: (i) psychosis, e.g.,        schizophrenia, in a patient suffering from depression; (2)        depression in a patient suffering from psychosis, e.g.,        schizophrenia; (3) mood disorders associated with psychosis,        e.g., schizophrenia or Parkinson's disease; (4) sleep disorders        associated with psychosis, e.g., schizophrenia or Parkinson's        disease; ad (5) substance a use disorders and/or        substance-induced disorders, optionally wherein the patient        suffers from residual symptoms of anxiety or anxiety disorder;    -   3.4 Method 3 or 3.1, wherein the central nervous system disorder        is psychosis, e.g., schizophrenia and said patient is a patient        suffering from depression;    -   3.5 Method 3 or 3.1, wherein the central nervous system disorder        is selected from obsessive-compulsive disorder (OCD),        obsessive-compulsive personality disorder (OCPD), social anxiety        disorder, panic disorder, agoraphobia, compulsive gambling        disorder, compulsive eating disorder, body dysmorphic disorder        and impulse control disorder;    -   3.6 Method 3 or 3.1, wherein the central nervous system disorder        is obsessive-compulsive disorder (OCD) or obsessive-compulsive        personality disorder (OCPD);    -   3.7 Method 3 or 3.1, wherein said central nervous system        disorder is depression and said patient is a patient suffering        from psychosis, e.g., schizophrenia, or Parkinson's disease;    -   3.8 Method 3 or 3.1, wherein the central nervous system disorder        is a sleep disorder;    -   3.9 Method 3.8, wherein said sleep disorder is sleep maintenance        insomnia, frequent awakening, and/or waking up feeling        unrefreshed;    -   3.10 Method 3.7 or 3.8, wherein the patient is also suffering        from depression;    -   3.11 Method 3.7, 3.8 or 3.9, wherein said patient is also        suffering from psychosis, e.g., schizophrenia;    -   3.12 Method 3.7-3.11, wherein said patient is also suffering        from Parkinson's disease;    -   3.13 Method 3 or 3.1, wherein the central nervous system        disorder is depression, anxiety or a combination thereof;    -   3.14 Method 3.13, wherein the depression and/or anxiety is acute        depression and/or acute anxiety;    -   3.15 Any of methods 3.13-3.14, wherein the central nervous        system disorder is acute anxiety (e.g., a short-duration anxious        episode associated with generalized anxiety disorder, panic        disorder, specific phobias, or social anxiety disorder, or        social avoidance);    -   3.16 Any of methods 3.13-3.15, wherein the central nervous        system disorder is acute depression (e.g., acute major        depressive episode, acute short-duration depressive episode,        acute recurrent brief depressive episode);    -   3.17 Any of methods 3.13-3.16, wherein the central nervous        system disorder is treatment resistant depression (e.g.,        depression which has not responded to treatment with an        antidepressant agent selected from a selective serotonin        reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI),        a tricyclic antidepressant, a monoamine oxidase inhibitor, a        norepinephrine reuptake inhibitor (NRI), a dopamine reuptake        inhibitor (DRI), an SRI/NRI, an SRI/DRI, an NRI/DRI, an        SRI/NRI/DRI (triple reuptake inhibitor), a serotonin receptor        antagonist, or any combination thereof);    -   3.18 Any of Methods 3.13-3.17, wherein the central nervous        system disorder is selected from bipolar depression and major        depressive disorder;    -   3.19 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with selective serotonin reuptake inhibitors (SSRIs),        such as citalopram, escitalopram, fluoxetine, fluvoxamine,        paroxetine, and sertraline;    -   3.20 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with serotonin-norepinephrine reuptake inhibitors        (SNRIs), such as venlafaxine, sibutramine, duloxetine,        atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran;    -   3.21 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with antipsychotic agents, such as clomipramine,        risperidone, quetiapine and olanzapine;    -   3.22 Any foregoing method, wherein said patient is unable to        tolerate the side effects of conventional antipsychotic drugs,        e.g., chlorpromazine, haloperidol, droperidol, fluphenazine,        loxapine, mesoridazine molindone, perphenazine, pimozide,        prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone and ziprasidone;    -   3.23 Any foregoing method, wherein said patient is unable to        tolerate the side effects of conventional antipsychotic drugs,        e.g., haloperidol, aripiprazole, clozapine, olanzapine,        quetiapine, risperidone, and ziprasidone;    -   3.24 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg;    -   3.25 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day;    -   3.26 Any of the foregoing methods wherein the central nervous        system disorder is dyskinesia, e.g., in a patient receiving        dopaminergic medications, e.g., medications selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, and anticholinergics,        e.g., levodopa;    -   3.27 Any of the foregoing methods wherein the central nervous        system disorder is Parkinson's disease;    -   3.28 Any of the foregoing methods wherein the central nervous        system disorder is Alzheimer's disease;    -   3.29 Any of the foregoing methods wherein the central nervous        system disorder is a seizure disorder (e.g., epilepsy,        generalized seizure disorder, status epilepticus);    -   3.30 Any of the foregoing methods wherein the central nervous        system disorder is a pain disorder (e.g., acute pain, chronic        pain, neuropathic pain and/or traumatic pain);    -   3.31 Method 3.30, wherein the patient is unable to tolerate the        side effects from conventional analgesics, such as non-steroidal        anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen,        naproxen, acetaminophen) or wherein such analgesics are        ineffective to treat the patient's pain;    -   3.32 Method 3.30 or 3.31, wherein the patient is unable to        tolerate the side effects from narcotic analgesics, such as        opiates and opioids (e.g., morphine codeine, oxycodone,        hydrocodone, meperidine, fentanyl) or wherein such agents are        ineffective to treat the patient's pain, or wherein such agents        are contraindicated (e.g., due to addiction, risk of addiction,        dependence, or tolerance, or drug-drug interactions);    -   3.33 Method 3, wherein the wherein the cardiac disorder is an        arrhythmia (e.g., ventricular arrhythmia, recurrent atrial        fibrillation, paroxysmal atrial fibrillation,        Wolff-Parkinson-White syndrome, increased QT interval),        ventricular tachycardia, recurrent tachyarrhythmias, or        myocardial infarction;    -   3.34 Any of the foregoing methods wherein the method comprises        administering the Compound of Formula 1 in free form;    -   3.35 Any of Methods 3.1 to 3.34, wherein the method comprises        administering the Compound of Formula 1 in salt form, e.g.,        pharmaceutically acceptable salt form;    -   3.36 Any of Methods 3.1 to 3.34, wherein the method comprises        administering any Compound of Formula 1 or 1.1 to 1.11;    -   3.37 Any preceding method, wherein the method comprises        administering a pharmaceutical composition comprising the        Compound of Formula 1 or any of 1.1 to 1.11, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   3.38 Method 3.37, wherein the pharmaceutical Composition is        Pharmaceutical Composition 2, or any of 2.1-2.9 or any of P.1 to        P.7;    -   3.39 Any preceding method wherein the method comprises        administering the Compound of Formula 1 or any of 1.1-1.11 in a        form formulated for controlled- and/or sustained-release of the        Compound over a period of from about 14 days, about 30 to about        180 days, preferably over the period of about 30, about 60 or        about 90 days;    -   3.40 Any foregoing method, wherein the method further comprises        concurrent administration of one or more additional therapeutic        agents, optionally wherein the dose of either the Compound of        the present disclosure and/or the one or more additional        therapeutic agents is provided at a lower dose compared to when        said Compound or agent is used as monotherapy.

The Compounds of the present disclosure, the Pharmaceutical Compositionsof the present disclosure or the Depot Compositions of the presentdisclosure may be used in combination with a second therapeutic agent,particularly at lower dosages than when the individual agents are usedas a monotherapy so as to enhance the therapeutic activities of thecombined agents without causing the undesirable side effects commonlyoccur in conventional monotherapy. For example, the Compounds of thepresent disclosure may be simultaneously, sequentially, orcontemporaneously administered with other anti-depressant,anti-psychotic, other hypnotic agents, and/or agents use to treatParkinson's disease or mood disorders. In another example, side effectsmay be reduced or minimized by administering a Compound of the presentdisclosure in combination with one or more second therapeutic agents infree or salt form, wherein the dosages of (i) the second therapeuticagent(s) or (ii) both Compound of the present disclosure and the secondtherapeutic agents, are lower than if the agents/compounds areadministered as a monotherapy. In a particular embodiment, the Compoundsof the present disclosure are useful to treat dyskinesia in a patientreceiving dopaminergic medications, e.g., selected from levodopa andlevodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors),dopamine agonists, and anticholinergics, e.g., such as are used in thetreatment of Parkinson's disease.

In some further embodiments of the present disclosure, thePharmaceutical Compositions of the present disclosure or the DepotCompositions of the present disclosure may be used in combination with asecond therapeutic agent, particularly at lower dosages than when theindividual agents are used as a monotherapy so as to enhance thetherapeutic activities of the combined agents without causing theundesirable side effects.

The Compounds of the present disclosure may be simultaneously,sequentially, or contemporaneously administered with any such additionaltherapeutic agents.

In further embodiments of the third aspect, the invention provides:

-   -   3.41 Method 3.40, wherein the one or more therapeutic agents are        selected from compounds that modulate GABA activity (e.g.,        enhances the activity and facilitates GABA transmission), a        GABA-B agonist, a 5-HT receptor modulator (e.g., a 5-HT_(1A)        agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist,        etc.), a melatonin receptor agonist, an ion channel modulator        (e.g., blocker), a serotonin-2 antagonist/reuptake inhibitor        (SARIs), an orexin receptor antagonist, an H3 agonist or        antagonist, a noradrenergic agonist or antagonist, a galanin        agonist, a CRH antagonist, human growth hormone, a growth        hormone agonist, estrogen, an estrogen agonist, a neurokinin-1        drug, an anti-depressant, an opiate agonist and/or partial        opiate agonist, an opiate antagonist and/or opiate inverse        agonist, and an antipsychotic agent, e.g., an atypical        antipsychotic agent, in free or pharmaceutically acceptable salt        form;    -   3.42 Method 3.40, wherein the therapeutic agent(s) is compounds        that modulate GABA activity (e.g., enhances the activity and        facilitates GABA transmission);    -   3.43 Method 3.42, wherein the GABA compound is selected from a        group consisting of one or more of doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   3.44 Method 3.40, wherein the therapeutic agent is an additional        5HT2a antagonist;    -   3.45 Method 3.44, wherein said additional 5HT2a antagonist is        selected from one or more of ketanserin, risperidone,        eplivanserin, volinanserin (Sanofi-Aventis, France),        pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli        Lilly), APD 125 (Arena Pharmaceuticals, San Diego, CA), and        AVE8488 (Sanofi-Aventis, France);    -   3.46 Method 3.40, wherein the therapeutic agent is a melatonin        receptor agonist;    -   3.47 Method 3.46, wherein the melatonin receptor agonist is        selected from a group consisting of one or more of melatonin,        ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162        (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II        Discovery) and agomelatine;    -   3.48 Method 3.40, wherein the therapeutic agent is an ion        channel blocker;    -   3.49 Method 3.48, wherein said ion channel blocker is one or        more of lamotrigine, gabapentin and pregabalin;    -   3.50 Method 3.40, wherein the therapeutic agent is an orexin        receptor antagonist;    -   3.51 Method 3.50, wherein the orexin receptor antagonist is        selected from a group consisting of orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline)        and a benzamide derivative;    -   3.52 Method 3.40, wherein the therapeutic agent is a serotonin-2        antagonist/reuptake inhibitor (SARI);    -   3.53 Method 3.52, wherein the serotonin-2 antagonist/reuptake        inhibitor (SARI) is selected from a group consisting of one or        more Org 50081 (Organon-Netherlands), ritanserin, nefazodone,        serzone and trazodone;    -   3.54 Method 3.40, wherein the therapeutic agent is a 5HTIa        agonist;    -   3.55 Method 3.54, wherein the 5HTIa agonist is selected from a        group consisting of one or more of repinotan, sarizotan,        eptapirone, buspirone and MN-305 (MediciNova, San Diego, CA);    -   3.56 Method 3.40, wherein the therapeutic agent is a        neurokinin-1 drug;    -   3.57 Method 3.56, wherein the neurokinin-1 drug is Casopitant        (GlaxoSmithKline);    -   3.58 Method 3.40, wherein the therapeutic agent is an        antipsychotic agent;    -   3.59 Method 3.58, wherein the antipsychotic agent is selected        from a group consisting of chlorpromazine, haloperidol,        droperidol, fluphenazine, loxapine, mesoridazine, molindone,        perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone        and paliperidone;    -   3.60 Method 3.40, wherein the therapeutic agent is an        anti-depressant;    -   3.61 Method 3.60, wherein the anti-depressant is selected from        amitriptyline, amoxapine, bupropion, citalopram, clomipramine,        desipramine, doxepin, duloxetine, escitalopram, fluoxetine,        fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine        sulfate, protriptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and venlafaxine;    -   3.62 Method 3.40, wherein the antipsychotic agent is an atypical        antipsychotic agent;    -   3.63 Method 3.62, wherein the atypical antipsychotic agent is        selected from a group consisting of clozapine, aripiprazole,        olanzapine, quetiapine, risperidone, ziprasidone, and        paliperidone;    -   3.64 Method 3. 40, wherein the therapeutic agent is selected        from the group consisting of modafinil, armodafinil, doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        ketanserin, risperidone, eplivanserin, volinanserin        (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, CA), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, MD), PD-6735 (Phase 11 Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitalopram, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenelzine sulfate, protriptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        venlafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine, molindone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone and paliperidone;    -   3.65 Method 3.40, wherein the therapeutic agent is an H3        agonist;    -   3.66 Method 3.40, wherein the therapeutic agent is an H3        antagonist;    -   3.67 Method 3.40, wherein the therapeutic agent is a        noradrenergic agonist or antagonist;    -   3.68 Method 3.40, wherein the therapeutic agent is a galanin        agonist;    -   3.69 Method 3.40, wherein the therapeutic agent is a CRH        antagonist;    -   3.70 Method 3.40, wherein the therapeutic agent is a human        growth hormone;    -   3.71 Method 3.40, wherein the therapeutic agent is a growth        hormone agonist;    -   3.72 Method 3.40, wherein the therapeutic agent is estrogen;    -   3.73 Method 3.40, wherein the therapeutic agent is an estrogen        agonist;    -   3.74 Method 3.40, wherein the therapeutic agent is a        neurokinin-1 drug;    -   3.75 Method 3.40, wherein the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalevo, Symmetrel, benztropine, biperiden, bromocriptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone;    -   3.76 Method 3.40, wherein the therapeutic agent is an opiate        agonist or partial opiate agonist, for example, a mu-agonist or        partial agonist, or a kappa-agonist or partial agonist,        including mixed agonist/antagonists (e.g., an agent with partial        mu-agonist activity and kappa-antagonist activity);    -   3.77 Method 3.76, wherein the therapeutic agent is        buprenorphine, optionally, wherein said method does not include        co-treatment with an anxiolytic agent, e.g., a GABA compound or        benzodiazepine;    -   3.78 Method 3.40, wherein the therapeutic agent(s) is an opiate        receptor antagonist or inverse agonist, e.g., a full opiate        antagonist, for example, selected from naloxone, naltrexone,        nalmefene, methadone, nalorphine, levallorphan, samidorphan,        nalodeine, cyprodime, or norbinaltorphimine;    -   3.79 Method 3.40, wherein the therapeutic agent is an        anticonvulsant, antiarrhythmic (e.g., Class I, Class II or Class        III antiarrhythmic), or an anesthetic;    -   3.80 Any of the foregoing methods, wherein the patient undergoes        concurrent or consecutive treatment with lumateperone.

In another aspect of the invention, the combination of a Compound of thepresent disclosure (e.g., Compound 1 or any of 1.1-1.11) and one or moresecond therapeutic agents as described in Methods 3.38 to 3.80 may beadministered to the patient as a Pharmaceutical Composition or a depotComposition as hereinbefore described. The combination compositions caninclude mixtures of the combined drugs, as well as two or more separatecompositions of the drugs, which individual compositions can be, forexample, co-administered together to a patient.

In a fourth aspect, the present disclosure provides for use of theCompound 1, or any of 1.1-1.11, or Pharmaceutical Composition 2, or anyof 2.1-2.9, in Method 3 or any of Methods 3.1-3.80.

In a fifth aspect, the present disclosure provides for use of theCompound 1, or any of 1.1-1.11, or Pharmaceutical Composition 2, or anyof 2.1-2.9, in the manufacture of a medicament for the treatment orprophylaxis of one or more central nervous system disorders as providedin any of Method 3 or 3.1-3.80.

In a sixth aspect, the present disclosure provides present disclosureCompound 1, or any of 1.1-1.11, or Pharmaceutical Composition 2, or anyof 2.1-2.9, for use in Method 3 or any of 3.1-3.80.

DETAILED DESCRIPTION OF THE INVENTION

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease and/or treatment of the cause of the disease. In particularembodiments, the words “treatment” and “treating” refer to prophylaxisor amelioration of symptoms of the disease.

The term “patient” may include a human or non-human patient.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition(“DSM-5”), defines “major depressive disorder” (MDD) as having five ormore of a set of symptoms during the same two-week period of time, whichsymptoms represent a change from the patient's previous functioning. Thefive symptoms are selected from depressed mood, markedly diminishedinterest or pleasure in almost all activities, significant weightchanges, insomnia or hyposomnia, psychomotor agitation or retardation,fatigue, feelings of worthlessness or excessive guilt, diminishedability to think or indecisiveness, and recurrent thoughts of death orsuicidal ideation, wherein each of such symptoms is present nearly everyday. At a minimum, MDD diagnosis requires at least depressed mood orloss of interest or pleasure as one of the five symptoms. MDD mayconsist of one or more “major depressive episodes” which can be spacedmany weeks or months apart (more than 2 weeks apart to qualify asseparate episodes). The DSM-5 notes that there is a risk of suicidalbehavior at all time during a major depressive episode.

By its nature, MDD is an acute disorder in so far as the DSM-5distinguishes it from “persistent depressive disorder”, in which apatient has many of the same symptoms as for MDD, but which persists forat least a 2-year period. In addition to MDD, the DSM-5 also defines a“short-duration depressive episode” as having a depressed affect and atleast four of the other symptoms which define MDD for at least 4 days,but less than 14 days. The DSM further defines “recurrent briefdepression” as the concurrent presence of depressed mood and at leastfour other symptoms of depression for 2 to 13 days at least once permonth, and persisting for at least 12 consecutive months. Thus,recurrent brief depression similarly consists of brief episodes ofdepression which recur regularly.

The DSM-5 also includes major depressive episodes as one of thediagnostic criteria for a patient suffering from bipolar disorder. Thus,a patient presenting a major depressive episode may be suffering fromeither major depressive disorder or bipolar disorder.

It is apparent that there are is a particular need for effectivetreatment of depression during the earliest stages of a major depressiveepisode, since each day of such episode can have profound consequencesfor a patient, yet typical SSRI anti-depressive agents take up to 2-4weeks for beneficial effects to appear. The same is true for treatmentof short duration depressive episodes as well as individual episodes ofrecurrent brief depression.

Thus, as used herein, the term “acute depression” refers to the initialperiod of what may be a brief or a chronic episode of depression (e.g.,lasting 2 days to 2 weeks, or 2 weeks to 2 months, or 2 months to 2years, or more). “Acute depression” may thus refer to the initial periodof a major depressive episode, a short-duration depressive episode, or arecurrent brief depressive episode. There is a particular need in theart for the treatment of such acute stages of depressive episodes. Atreatment initiated during this acute phase of depression may becontinued indefinitely in those patients which respond thereto.

The DSM-5 defines a variety of anxiety disorders, including generalizedanxiety disorder, panic disorder, social anxiety disorder, and specificphobias. Like the depressive disorders discussed above, anxietydisorders can be marked by recurrent episodes of short duration, such aspanic attacks, which may persist over the course of a chronic disorder.For example, generalized anxiety disorder is defined by the DSM-5 torequire excessive anxiety and worry occurring more days that not for atleast 6 months, about a number of events or activities. A panic attackis defined as an abrupt surge of intense fear or intense discomfort thatreaches a peak within minutes, but it can repeatedly recur in responseto either expected stimuli or unexpected stimuli. Thus, as for thedepressive disorders described above, there is a need for rapidly-actinganxiolytic agents that can treat the symptoms of anxiety or panic, yetsome of the most common treatments for anxiety disorders are the SSRIsand other antidepressant agents which take 2-4 weeks to provide relief.

As used herein, “acute anxiety” refers to any short-duration episode ofanxiety, e.g., lasting from one day or less to one week, which may bepart of a chronic course of anxiety (e.g., lasting 2 days to 2 weeks, or2 weeks to 2 months, or 2 months to 2 years, or more). “Acute anxiety”may thus include a panic attack or any specific instance of an anxiousresponse to triggering stimuli or events (e.g., to the stimuli whichtrigger a specific phobia, the events which trigger social anxiety orgeneralized anxiety). There is a particular need in the art for thetreatment of such acute stages of anxious episodes. A treatmentinitiated during this acute phase of anxiety may be continuedindefinitely in those patients which respond thereto.

Social avoidance can be a critical and debilitating symptom in patientssuffering from anxiety disorders, especially social anxiety disorder, aswell as in patients suffering from traumatic anxiety disorders. Socialavoidance is often one of the key determinants of whether a person witha severe anxiety disorder is capable of maintaining familialrelationships or employment relationships. It has been unexpectedlyfound that certain substituted fused gamma carbolines having 5-HT_(2A)and dopamine receptor activity, such as lumateperone, are effective intreating the emotional experience symptoms of psychiatric disorders(e.g., the emotional experience negative symptoms of schizophrenics).Negative symptoms of schizophrenia can be divided into two categories:emotional experience (e.g., emotional withdrawal, passive socialwithdrawal, active social avoidance) and emotional expression (e.g.,blunted effect, poor rapport, lack of spontaneity, and motorretardation). In two clinical studies of patients with acute exacerbatedschizophrenia, administration of lumateperone once daily (60 mg P.O.),for up to 28 days, resulted in a significant and unexpected improvementin symptoms of emotional experience compared to placebo. These are thesymptoms that are most highly correlated with interpersonal functioning.As such, such compounds, including the compounds of Formula I, may behighly effective in treating the emotional experience symptoms of otherpsychiatric disorders, such as social anxiety disorders, or any otherpsychiatric disorders in which social withdrawal and social avoidanceare symptoms.

Substance-use disorders and substance-induced disorders are the twocategories of substance-related disorders defined by the Fifth Editionof the DSM (the Diagnostic and Statistical Manual of Mental Disorders,DSM-5). A substance-use disorder is a pattern of symptoms resulting fromuse of a substance which the individual continues to take, despiteexperiencing problems as a result. A substance-induced disorder is adisorder induced by use if the substance. Substance-induced disordersinclude intoxication, withdrawal, substance induced mental disorders,including substance induced psychosis, substance induced bipolar andrelated disorders, substance induced depressive disorders, substanceinduced anxiety disorders, substance induced obsessive-compulsive andrelated disorders, substance induced sleep disorders, substance inducedsexual dysfunctions, substance induced delirium and substance inducedneurocognitive disorders.

The DSM-5 includes criteria for classifying a substance use disorder asmild, moderate or severe. In some embodiments of the methods disclosedherein, the substance use disorder is selected from a mild substance usedisorder, a moderate substance use disorder or a severe substance usedisorder. In some embodiments, the substance use disorder is a mildsubstance use disorder. In some embodiments, the substance use disorderis a moderate substance use disorder. In some embodiments, the substanceuse disorder is a severe substance use disorder.

Anxiety and depression are highly prevalent co-morbid disorders inpatients undergoing treatment of substance use or substance abuse.

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

The term “pharmaceutically acceptable diluent or carrier” is intended tomean diluents and carriers that are useful in pharmaceuticalpreparations, and that are free of substances that are allergenic,pyrogenic or pathogenic, and that are known to potentially cause orpromote illness. Pharmaceutically acceptable diluents or carriers thusexclude bodily fluids such as example blood, urine, spinal fluid,saliva, and the like, as well as their constituent components such asblood cells and circulating proteins. Suitable pharmaceuticallyacceptable diluents and carriers can be found in any of severalwell-known treatises on pharmaceutical formulations, for exampleAnderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins, 2000; and Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety.

The terms “purified,” “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g., from a reaction mixture),or natural source or combination thereof. Thus, the term “purified,” “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization, LC-MS andLC-MS/MS techniques and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell known to the skilled artisan. Depending on the nature and use ofthe compound and the process or processes used for purification, theterm “purified” may reflect an actual purity of, for example, at least90% pure form, or at least 95%, or at least 96%, or at least 97%, or atleast 98%, or at least 99%, or at least 99.5%, or at least 99.9%.

The term “concurrently” when referring to a therapeutic use meansadministration of two or more active ingredients to a patient as part ofa regimen for the treatment of a disease or disorder, whether the two ormore active agents are given at the same or different times or whethergiven by the same or different routes of administrations. Concurrentadministration of the two or more active ingredients may be at differenttimes on the same day, or on different dates or at differentfrequencies.

The term “simultaneously” when referring to a therapeutic use meansadministration of two or more active ingredients at or about the sametime by the same route of administration.

The term “separately” when referring to a therapeutic use meansadministration of two or more active ingredients at or about the sametime by different route of administration.

The Compounds of the present disclosure are intended for use aspharmaceuticals, therefore pharmaceutically acceptable salts arepreferred. Salts which are unsuitable for pharmaceutical uses may beuseful, for example, for the isolation or purification of free Compoundsof the Invention and are therefore also included within the scope of thecompounds of the present disclosure.

The Compounds of the present disclosure may comprise one or more chiralcarbon atoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diastereomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or(R,S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

It is also intended that the compounds of the present disclosureencompass their stable and unstable isotopes. Stable isotopes arenonradioactive isotopes which contain one additional neutron compared tothe abundant nuclides of the same species (i.e., element). It isexpected that the activity of compounds comprising such isotopes wouldbe retained, and such compound would also have utility for measuringpharmacokinetics of the non-isotopic analogs. For example, the hydrogenatom at a certain position on the compounds of the disclosure may bereplaced with deuterium (a stable isotope which is non-radioactive).Examples of known stable isotopes include, but not limited to,deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes, which areradioactive isotopes which contain additional neutrons compared to theabundant nuclides of the same species (i.e., element), e.g., ¹²³I, ¹³¹I,¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundant species of I, Cand F. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. In addition, the substitution of atoms of having the naturalisotopic distributing with heavier isotopes can result in desirablechange in pharmacokinetic rates when these substitutions are made atmetabolically liable sites. For example, the incorporation of deuterium(²H) in place of hydrogen can slow metabolic degradation when theposition of the hydrogen is a site of enzymatic or metabolic activity.

The Compounds of the present disclosure may be included as a depotformulation, e.g., by dispersing, dissolving or encapsulating theCompounds of the Invention in a polymeric matrix as described herein,such that the Compound is continually released as the polymer degradesover time. The release of the Compounds of the Invention from thepolymeric matrix provides for the controlled- and/or delayed- and/orsustained-release of the Compounds, e.g., from the pharmaceutical depotcomposition, into a subject, for example a warm-blooded animal such asman, to which the pharmaceutical depot is administered. Thus, thepharmaceutical depot delivers the Compounds of the Invention to thesubject at concentrations effective for treatment of the particulardisease or medical condition over a sustained period of time, e.g.,14-180 days, preferably about 30, about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxyfatty acid and derivatives thereof or other agentssuch as polylactic acid, polyglycolic acid, polycitric acid, polymalicacid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ringopening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyricacid-glycolic acid copolymer, polylactic acid-polyethyleneglycolcopolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymerof an alkyl alpha-cyanoacrylate (for example poly(butyl2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethyleneoxalate or polytetramethylene oxalate), a polyortho ester, apolycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly(lactic acid), or PLA). Most preferably, the polymer isthe biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 Daltons, preferably about 150,000 Daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerization with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e.g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e.g., poly (d, 1-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot compositions of the invention (e.g., Compositions 6 and6.1-6.10, in a polymer matrix) as hereinbefore described may comprisethe polymer in the form of microparticles or nanoparticles, or in aliquid form, with the Compounds of the Invention dispersed orencapsulated therein. “Microparticles” is meant solid particles thatcontain the Compounds of the Invention either in solution or in solidform wherein such compound is dispersed or dissolved within the polymerthat serves as the matrix of the particle. By an appropriate selectionof polymeric materials, a microparticle formulation can be made in whichthe resulting microparticles exhibit both diffusional release andbiodegradation release properties.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of the Invention encapsulated therein.In the solvent extraction method, the Compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. Nos. 4,389,330 and 4,530,840.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of the Invention and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Pub. No. 2008/0069885, thecontents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of the present disclosure incorporated inthe microparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of the present disclosure per totalweight of microparticle.

The pharmaceutical depot compositions may comprise apharmaceutically-acceptable diluent or carrier, such as a water misciblediluent or carrier.

Details of Osmotic-controlled Release Oral Delivery System compositionmay be found in U.S. Pub. No. 2009/0202631, the contents of which areincorporated by reference in its entirety.

A “therapeutically effective amount” is any amount of the Compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g., on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the Compound of the Invention for administration (whetheradministered as a free base or as a salt form) refers to or is based onthe amount of the Compound of the Invention in free base form (i.e., thecalculation of the amount is based on the free base amount).

Compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally, but are preferably administered orally.In certain embodiments, the Compounds of the Invention, e.g., in depotformulation, are preferably administered parenterally, e.g., byinjection.

In general, satisfactory results for Method 3 et seq., as set forthabove, are indicated to be obtained on oral administration at dosages ofthe order from about 1 mg to 100 mg once daily, preferably 2.5 mg-50 mg,e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily,preferably via oral administration. In some embodiments, particularlyrelated to sleep disorders, satisfactory results are obtained on oraladministration of dosages of the order from about 2.5 mg-5 mg, e.g., 2.5mg, 3 mg, 4 mg or 5 mg, of a Compound of the Invention, in free orpharmaceutically acceptable salt form, once daily, preferably via oraladministration.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg. Duration of action of the Compounds of the presentdisclosure may be controlled by manipulation of the polymer composition,i.e., the polymer:drug ratio and microparticle size. Wherein thecomposition of the invention is a depot composition, administration byinjection is preferred.

The pharmaceutically acceptable salts of the Compounds of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free base forms of these compoundswith a stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred.

Pharmaceutical compositions comprising Compounds of the presentdisclosure may be prepared using conventional diluents or excipients (anexample include, but is not limited to sesame oil) and techniques knownin the galenic art. Thus, oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

The prior art discloses numerous synthetic methods applicable generallyto fused heterocycle gamma-carbolines related to the compounds disclosedherein. The skilled artisan may follow or adapt procedures as variouslydescribed in U.S. Pat. RE39,680; U.S. Pat. Nos. 7,183,282; 8,309,722;9,751,883; and U.S. Patent Pub. 2017/0319580.

Diastereomers of prepared compounds can be separated by, for example,HPLC using CHIRALPAK® AY-H, ⁵p, 30×250 mm at room temperature and elutedwith 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can bedetected at 230 nm to produce 98-99.9% ee of the diastereomer.

Example 1: Synthesis of4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido┌3′,4′:4,5┐pyrrolo┌1,2,3-de┐quinoxalin-8(7H)-yl)-1-(4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)phenyl)butan-1-one

A suspension of(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline(ca. 11.8 g, ca. 50 mmol), 4-chloro-4′-fluorobutyrophenone (15.0 g, 74.8mmol), triethylamine (30 mL, 214 mmol), and potassium iodide (12.6 g, 76mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7hours. After filtration and evaporation of the solvent, 200 ml of DCM isadded. The DCM solution is washed with brine, dried (Na₂SO₄) andconcentrated to approximately 55 ml. The concentrated solution is addeddropwise to 600 ml of 0.5N HCl in ether solution. The solid is filteredoff and washed with ether and then dissolved in water. The resultingaqueous solution is basified with 2N NaOH and extracted with DCM. TheDCM layers are combined, washed with brine (2×200 mL) and dried(Na₂SO₄). Evaporation of the solvent and chromatography of the residueover silica gel gives the title product.

Example 2: Receptor Binding Profile of Compound of Examples 1

Receptor binding is determined for the Compounds of Example 1. Thefollowing literature procedures are used, each of which reference isincorporated herein by reference in their entireties: 5-HT_(2A): Bryant,H. U. et al. (1996), Life Sci., 15:1259-1268; D2: Hall, D. A. andStrange, P. G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, Q. Y.et al. (1990), Nature, 347:76-80; SERT: Park, Y. M. et al. (1999), Anal.Biochem., 269:94-104; Mu opiate receptor: Wang, J. B. et al. (1994),FEBS Lett., 338:217-222.

The compound of Example 1 is tested at a concentration of 1.0 μM in DMSOsolution. Compound binding is calculated as the percent inhibition ofthe binding of a radioactively labeled ligand specific for each target.The control ligands are radiolabeled forms of SCH 23390 (for D1),7-hydroxy-DPAT (for D2S), racemic DOI (for 5-HT_(2A) and 5-HT_(2B)),veratridine (for sodium channel site 2), protriptyline (for NET) andimipramine (for SERT).

In general, the results are expressed as a percent of control specificbinding:

$\frac{{measured}{specific}{binding}}{{control}{specific}{binding}} \times 100$

and as a percent inhibition of control specific binding:

$100 - \left( {\frac{{measured}{specific}{binding}}{{control}{specific}{binding}} \times 100} \right)$

obtained in the presence of the test compound (compound of Example 1).

The following receptor affinity results are obtained (% inhibition):

Compound 1 Receptor (Ex. 1) SERT (antagonist binding) 99.9% 5-HT_(2A)(agonist binding) 90.8% 5-HT_(2B) (agonist binding) 87.0% D2S (agonistbinding)  80.63% D1 (antagonist binding) 52.3% Sodium channel (site 287.0% antagonist binding) NET (antagonist binding) 82.9%

These results show that the compound of the present disclosure has aunique and unexpected receptor binding profile.

Further pharmacology studies are conducted to determine IC₅₀ values forreceptor binding to the 5-HT_(2A) receptor, D1 receptor, and SERT. Foreach study, the compound of Example 1 is tested at a range ofconcentrations and compound binding at each concentration is calculatedas the percent inhibition of the binding of a radioactively labeledligand specific for the target. The control ligands are radiolabeledforms of 7-hydroxy-DPAT (for D2S), racemic DOI (for 5-HT_(2A)), andimipramine (for SERT). The IC₅₀ value is determined by non-linearregression analysis of the competition curve generated with meanreplicate values using Hill Equation curve fitting:

$Y = {D + \frac{\left\lceil {A - D} \right\rceil}{1 + \left( {C/{IC}_{50}} \right)^{nH}}}$

wherein Y is specific binding, A is the left asymptote of the curve, Dis the right asymptote of the curve, C is the compound concentration,and nH is the slope factor. Ki values are calculated using the ChengPrusoff equation:

$K_{i} = \frac{{IC}_{50}}{\left( {1 + {L/K_{D}}} \right)}$

wherein L is the concentration of the radioligand in the assay, andK_(D) is the affinity of the radioligand for the receptor. A scatchardplot is used to determine the K_(D).

Using the above methods, the following Ki and IC₅₀ results are obtained:

Compound 1 Compound 1 (Ex. 1) (Ex. 1) Receptor K_(i) IC₅₀ SERT(antagonist binding) 1.3 nM 2.9 nM 5-HT_(2A) (agonist binding) 51 nM 68nM D2S (agonist binding) 72 nM 180 nM

These results show that the compound of the present disclosure has aunique and unexpected receptor binding profile.

1. (canceled)
 2. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier in admixture with acompound of Formula I:

in free base or pharmaceutically acceptable salt form, wherein thecomposition further comprises a compound of Formula II:

in free base or pharmaceutically acceptable salt form.
 3. (canceled) 4.The pharmaceutical composition according to claim 2, wherein thecomposition is formulated as a sustained or delayed release composition.5. The pharmaceutical composition according to claim 2, wherein thecomposition further comprises a polymeric matrix.
 6. The pharmaceuticalcomposition according to claim 5, wherein the polymeric matrix comprisesa biodegradable poly(D,L-lactide-co-glycolide) polymer.
 7. A method for(a) inhibiting serotonin (5-hydroxytryptamine) receptor activity, (b)modulating dopamine D2 receptor function, (c) inhibiting serotoninreuptake transporter activity, (d) inhibiting norepinephrine reuptaketransporter activity, or (e) inhibiting sodium ion channel activity, ina patient in need thereof, wherein the method comprises theadministration to the patient of a therapeutically effective amount ofthe pharmaceutical composition according to claim
 2. 8. The methodaccording to claim 7, wherein the patient has a cardiac disorder or acentral nervous system disorder involving the serotonin(5-hydroxytryptamine) receptor, the dopamine D2 receptor system, theserotonin reuptake transporter, the norepinephrine reuptake transporter(NET), and/or the sodium ion channel.
 9. The method according to claim7, wherein the central nervous system disorder is a disorder selectedfrom the group consisting of an agitation in autism, an agitation indementia, agoraphobia, anxiety, attention deficit disorder, bodydysmorphic disorder, compulsive eating disorder, compulsive gamblingdisorder, dementia, depression, a gastrointestinal disorder,hypochondriasis, impulse control disorder, kleptomania, migraine, a mooddisorder, a neurodegenerative disorder, obesity, an obsessive-compulsivedisorder, orthostatic intolerance, a pain disorder, pathologicalgrooming disorder, psychosis, pyromania, schizophrenia, a sexualdisorder, a sleep disorder, a social phobia, and a substance abusedisorder, or a combination thereof.
 10. (canceled)
 11. (canceled) 12.The method according to claim 97, wherein the central nervous systemdisorder is anxiety or depression, or a combination thereof.
 13. Themethod according to claim 12, wherein the anxiety or depression is acuteanxiety or acute depression.
 14. The method according to claim 13,wherein the acute anxiety is selected from the group consisting of ashort-duration anxious episode associated with generalized anxietydisorder, a short-duration anxious episode associated with panicdisorder, a short-duration anxious episode associated with socialanxiety disorder, a short-duration anxious episode associated withsocial avoidance, and a short-duration anxious episode associated with aspecific phobia.
 15. The method according to claim 13, wherein the acutedepression is selected from the group consisting of an acute majordepressive episode, an acute recurrent brief depressive episode, and anacute short-duration depressive episode.
 16. The method according toclaim 13, wherein the central nervous system disorder is treatmentresistant depression.
 17. The method according to claim 9, wherein thecentral nervous system disorder is bipolar depression and/or majordepressive disorder.
 18. The method according to claim 9, wherein thecentral nervous system disorder is a seizure disorder.
 19. The methodaccording to claim 9, wherein the central nervous system disorder is apain disorder.
 20. The method according to claim 8, wherein the cardiacdisorder is selected from the group consisting of an arrhythmia,myocardial infarction, a recurrent tachyarrhythmia, and a ventriculartachycardia.
 21. (canceled)
 22. The pharmaceutical composition accordingto claim 4, wherein the sustained release or delayed release compositionis an injectable depot.
 23. The pharmaceutical composition according toclaim 6, wherein the polymeric matrix is comprised within a microsphere.24. The method according to claim 16, wherein the treatment resistantdepression is depression which has not responded to treatment with anantidepressant agent selected from the group consisting of a dopaminereuptake inhibitor (DRI), a monoamine oxidase inhibitor, anorepinephrine reuptake inhibitor (NRI), a norepinephrinereuptake/dopamine reuptake inhibitor (NRI/DRI), a serotonin receptorantagonist, a serotonin reuptake inhibitor (SRI), and a tricyclicantidepressant, or a combination thereof.
 25. The method according toclaim 24, wherein the serotonin reuptake inhibitor (SRI) is selectedfrom the group consisting of a selective serotonin reuptake inhibitor(SSRI), a serotonin reuptake/dopamine reuptake inhibitor (SRI/DRI), aserotonin reuptake/norepinephrine reuptake inhibitor (SRI/NRI), and aserotonin reuptake/norepinephrine reuptake/dopamine reuptake inhibitor(SRI/NRI/DRI).
 26. The method according to claim 20, wherein thearrhythmia is selected from the group consisting of an increased QTinterval, a paroxysmal atrial fibrillation, a recurrent atrialfibrillation, a ventricular arrhythmia, and Wolff-Parkinson-Whitesyndrome.